The development of rapid, accurate diagnosis methods for the detection of pathogen microbes and disease signature bio-molecules are longstanding goals of medical scientific researchers. After Sep. 11, 2001, this has become a high priority biodefense requirement in national defense. Various techniques have been developed in an attempt to achieve this goal.
Current technologies of detecting biological substances include a cell culture method, an immune assay method, and a gene amplification method. These technologies have limitations because of unacceptable chances of false positives and the further requirements of expensive equipment, highly skilled users and long detection time.
A cell culture method typically detects bacteria by culturing bacteria in liquid media or on the surface of media solidified by agar. The disadvantages of the cell culture method include low sensitivity and detection generally takes an unacceptably long time. Some bacteria and virus strains such as mycoplasma species are difficult to culture because they are intracellular microorganisms. Some microorganisms take an extremely long time to culture. For example, it takes six weeks to culture bacteria causing Lyme's Disease for its detection.
An immune assay method detects infectious agents by observing antibody-antigen reaction. This method has been commonly used in clinical diagnosis. One of the disadvantages of the immune assay method is that there is a cross-reaction in the immune detection. The other disadvantage is unacceptably low sensitivity. Thus, a large amount of target agent is required so that this method is not effective to detect a small amount of antigen or molecules such as a few anthrax spores.
A gene amplification method detects a target DNA by a polymerase chain reaction. An advantage of this method is that it can detect a very small amount of a target DNA. It has extremely high sensitivity compared to an immune assay method. A disadvantage of the gene amplification method is that it provides an unacceptable level of false positive observations, which are caused by contamination or mismatch annealing in the gene amplification process. Moreover, this method is expensive in that it requires highly skilled persons and specialized equipment.
Most of the biosensors available today are optical sensors. A few of them have good specificity and sensitivity. However, since these optical sensors require complex techniques, their application is limited. Moreover, these optical sensors require multiple labeling processes done by skilled professionals. Detection by the optical sensors and the data analysis requires specific and expensive instruments.
Electrochemical technologies have been used in the development of bio-sensors for the past 15 years. These technologies allow a near real time detection and relatively lower cost detection instrument compared to optical bio-sensors (see U.S. Pat. No. 6,391,624 to Megerle, U.S. Pat. No. 5,942,388 To Willner, et al. and U.S. Pat. No. 4,585,652 to Miller, et al). However, these methods depend on oxidation and reduction reaction in the detection process. In most cases, target agents or the capture molecules, (ie. probes,) need to be modified or labeled with redox elements, in order to create such a reaction. It is a complicated chemical process.
Therefore, simple detection processes and low cost devices need be developed. Recently, semiconductor technologies that produce computer chips are considered and used with biotechnology in the development of bio-sensor devices. This invention focuses on a mechanism, which reports biological interaction events as electronic signals.